Fanconi anemia (FA) is a disease resulting from autosomal recessive defects in any of at least eight genes, indicating a complex interaction or pathways. The disease is characterized by marrow by marrow failure. The disease is characterized by marrow failure, chromosome instability, increased incidence of leukemia and developmental defects. Cells from patients with FA are hypersensitive to DNA crosslinking agents, so the role of the FA proteins in crosslink repair is an important question. Project 1 will study the molecular action of the FA genes and the relation of crosslink repair to the pathogenesis of the disease. There are three goals. (1) Our PPG group has narrowed the search for the FANCD gene to a small region of chromosome 3p26. Isolation and characterization of this gene and its product will be primary near term goal for this project with Project 2. (2) After isolation of the FANCD gene, definition of the action of the FANCD protein and its possible role in crosslink repair will be the goal . FANCD protein localization and interactions will be tested. Proteins which interact with FANCD will be evaluated as candidates for "new" FA gene products. (3) As a third objective, an alternative approach to understanding A will be taken. Mouse mutants in two genes which are crosslink repair-specific, SNMl and REV3 will be constructed, in order to determine phenotypic similarities to FA and to test the hypothesis that DNA crosslink repair defects are causative in the pathogenesis of FA.